ITMI940506A1 - ACTIVE QUINZOLYLAMINIC DERIVATIVES AS ALPHA-ANTAGONISTS - Google Patents

Abstract

PCT No. PCT/EP95/01001 Sec. 371 Date Sep. 17, 1996 Sec. 102(e) Date Sep. 17, 1996 PCT Filed Mar. 17, 1995 PCT Pub. No. WO95/25726 PCT Pub. Date Sep. 28, 1995New qunazolinyl-amino derivatives useful as alpha 1-adrenoreceptor blockers are described. These compounds can be used as therapeutic agents for treating afflictions and diseases related to hyperactivity of the alpha -adrenergic system, such as, for example, arterial hypertension, prostate benign hyperplasia, high intraocular pressure and hpercholesterolemia. Processes for the preparation of the above said compounds are also described.

Description

DESCRIPTION of the invention having as title:

ACTIVE QUINZOLYLAMINE DERIVATIVES AS ALPHA-ANTAGONISTS

The present invention relates to new derivatives of 4-amino-6,7-dimethoxyquinazoline with α-antagonist activity, their mixtures of isomers, the single enantiomers, their addition salts with pharmacologically acceptable acids and the pharmaceutical compositions which contain.

Many of the known derivatives of quinazoline, in particular those which include the piperazine group in their structure, are endowed with antihypertensive or hypotensive activity.

For example, in US patent 3,511,836 quinazolinic derivatives endowed with antihypertensive activity are described. In particular, among these, l1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4 - (2-furanylcarbonyl) piperazine (Prazosin) is currently

marketed for this type of therapy.

In US patent US 4,026,894, on the other hand, other structurally similar compounds are described, including 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4 - [(tetrahydro-2-furanyl) -carbonyl)] piperazine (Terazosin) has found use both as

hypotensive, both in the therapy of benign prostatic hyperplasia (BPH). During the treatment carried out with these compounds, however, various undesirable side effects are encountered such as: headache, drowsiness, asthenia, nausea and palpitation. In some cases postural effects have been reported in addition to the symptoms typically associated with the decrease in blood pressure, i.e. dizziness, and feeling of lightheadedness.

The need is therefore still felt to have substances which, while being therapeutically active against the aforementioned disorders, at the same time show a lower incidence of side effects.

It has now been found, and it is the object of the present invention, that by suitably modifying the substituents of the piperazine ring, derivatives still endowed with good affinity for the α1-adrenergic receptors are obtained which also show to possess, with respect to the already known products , less toxicity '.

The substances of the invention have the general formula I

where B represents one of the following groups:

in which:

alternatively represents a bond, of valence, the -CO- group or the -CONH- group, each of which is represented meaning that the left side is the part connected to the heterocyclic ring and the right side the part connected to the alkyl chain ; and R2 are the same or different and independently represent a hydrogen atom or a linear or branched alkyl group having from 1 to 4 carbon atoms; n is 0 or 1; m is an integer from 0 to 4 and R represents an aryl or diarylmethyl or aroll or aryl (hydroxy) methyl or alkyloxycarbonyl or aryloxy group unsubstituted or optionally substituted with one or more alkoxyl, linear or branched alkyl groups having from 1 with 4 carbon atoms or a group of formula -CONHR3 or -N (R4) R5 where:

- R3 represents a hydrogen atom or a linear or branched alkyl group, having from 1 to 4 atoms of

carbon, or an aryl group;

- R4 and R5 can be the same or different and independently represent a hydrogen atom or a linear or branched alkyl group having from 1 to 4 carbon atoms or a benzyloxycarbonyl or methanesulfonyl or benzyloxycarbonylglycinoyl group;

in which:

Alk represents a linear alkyl group having 1 to 3 carbon atoms e

Z represents a phenyl or benzhydryl group or

4- (2-methoxyphenyl) -1-piperazinite;

The invention also includes the enantiomers, diastereomers, N-oxides and addition salts of these compounds with pharmaceutically acceptable acids.

The compounds of the invention have been subjected to pharmacological tests to highlight their interest as substances with potential therapeutic activity. In particular, their antagonistic activity of α1-type adrenergic receptors was determined, finding that this activity occurs both "in vivo" and "in vitro". At the same time, the acute toxicity tests suggested a probable lower incidence of unwanted side effects.

The foregoing invites the potential use of these compounds in the treatment of disorders involving hyperactivity of the α-adrenergic system such as, for example, arterial hypertension and benign prostatic hyperplasia.

SUMMARY OF THE COMPOUNDS OF THE INVENTION

In general, the compounds of formula I can be prepared by condensation of the 2-haloquinazolines of formula II:

where X represents a halogen atom, with aminicl derivatives of formula III:

in which B represents any of the groups B1 to B5 defined above, with the exception of group B1 when R represents -N (R4) R5 where R4 and R5 are simultaneously or independently H or alkyl.

Such condensation can be carried out in high boiling polar solvents (e.g. isoamyl alcohol, DMF) at 120 ° C / reflux as illustrated in Examples 1, 2, 21, 22 and 28-33 below.

Compounds in which B represents a group B1 can alternatively be prepared by condensation of the quinazoline derivative of formula IV:

with carboxylic acids of formula <V>:

where R, R1, R2, n and m have the meanings defined above, or with reactive derivatives of the aforementioned acids, such as the corresponding chlorides.

These condensations are carried out in the presence of a condensing agent (e.g. N.N-dicyclohexylcarbidiimide) and a promoting agent (e.g. 4-dimethylaminopyridine) in aprotic and / or chlorinated solvent (e.g. DMF, CHCl3) at 0 / + 140 ° C as illustrated in Examples 3-6 11-13, 15, 17, 18 and 23-27. If reactive derivatives of acids are used, the reactions are carried out at 0 / + 80 ° C in the presence of a tertiary amine (eg triethylamine) or other acceptor of the acid formed.

An alternative method is illustrated in Example 10 and consists in reacting the quinazoline derivative of formula IV with amines of formula VI:

(YOU)

where R, R1 R2, n and m have the meanings defined above, in the presence of N, N'-carbonyldiimidazole in an aprotic solvent (eg tetrahydrofuran) at 0 / + 50 ° C.

Compounds in which R represents an aryl (hydroxy) methyl group can be prepared by reduction of the corresponding aroyl derivatives using reducing agents (e.g. sodium borohydride) in protid solvents (e.g. water, methanol) at 0 / + 40 ° C (Examples 14 and 16).

Compounds in which R is a group -N (R4) R5, where R4 or R, respectively represent a hydrogen atom, can be prepared by hydrolysis of the corresponding compounds in which R4 or R5 are the COOCH2C6H5 group.

These reactions, illustrated in Examples 7 and 8, are carried out in protic solvents (e.g. acetic acid) in the presence of a strong acid (e.g. hydrobromic acid) at 0 / + 40 ° C as indicated by T. W. Greene, Protective Groups in Organic Synthesis, p. 335, Wiley Interscience (1991) or according to other methods found in the same reference.

Compounds in which R represents a group -N (R4) R5, where R4 and R5 are respectively a hydrogen atom and a methanesulfonyl group can be prepared by acylation with methanesulfonyl chloride of the corresponding compounds in which R4 = R5 = H. The reaction ( Example 9) is carried out in aprotic solvents (eg pyridine) in the presence of a base (eg triethylamine) at 0 / + 40 ° C.

DETAILED PREPARATION OF INTERMEDIATES

1- (2-Phenoxy-2-methylpropionyl) piperazine hydrochloride

(Intermediate I)

To the solution of 17.2 g of anhydrous piperazine in 50 mL of 95% EtOH and 22 mL of H2O, 3.37 g of 48% HBr are dropped in about 10 'and subsequently, in about 40 minutes and at T.A., a solution of 9.93 g of 2-phenoxy-2-methylpropionyl chloride (prepared according to: Bull. Soc. Chim. Fr. 1956. 776-783) in 70 mL of THF. The suspension is stirred 2 h at the same temperature and 3 h under reflux, diluted with 130 mL of THF, cooled and filtered from the precipitated piperazine salts. The filtrate is evaporated to dryness, the residue is taken up with 120 mL of H2O and 35 mL of HCl 2 N and extracted with Et2O; the aqueous phase is alkalized with 40 mL of conc. NaOH. and extracted with Et2O (4x50 mL). The ether phase, previously dried, is acidified with HCl in Et2O about 3 N and the precipitate collected by filtration is crystallized from EtOH to give 5.98 g (42% of theory) of the title compound; m.p .: 236-238 ° C.

1- [2-Methyl-2- (2-methoxyphenoxy) Dropionylpiperazine hydrochloride hydrate (Intermediate II)

To the boiling solution of 10.5 g of 2- (2-methoxyphenoxy) -2-methylpropionic acid, prepared according to: Gazz. Chim. It. 93, 335-338 (1963), in 50 mL of anhydrous CHCl3 a solution of 5.4 mL of SOCl2 in 20 mL of anhydrous CHCl3 is dropped into 50 mL of anhydrous CHCl3 and heated under reflux for 2 h. The residue obtained from the dry evaporation of the reaction mixture is used, instead of 2-phenoxy-2-methyl - propionyl chloride, to prepare the title compound according to the method described for intermediate I. After crystallization from methylethyl ketone 6.3 g (34% of theory) of intermediate II are obtained; m.p. 95-98 ° C.

2-methoxy-6-isopropylphenoxyacetic acid (Intermediate III)

To a mixture of 20 g of NaOH in tablets, 30 mL of H2O, 1.1 g of triethylbenzylammonium chloride, 8.4 g of 2-isopropyl-6-methoxyphenol (prepared according to: Tetr. Lett. 38, 1397-1404 ( 1982)) and 40 mL of toluene is dropped, at T.A. and in about 15 ', a solution of 11.1 mL of ethyl bromoacetate in 10 mL of toluene. The mixture is stirred vigorously at the same temperature for 2 h, then for 2 h at 60-65 ° C and for 6.5 h under reflux, during which a solution of 6 mL of ethyl bromoacetate in 10 mL of toluene is added. At the end, the mixture is diluted with 250 mL of H2O, the aqueous phase is separated and acidified with conc. HCl; the emulsified precipitate is extracted with Et2O (3 x 50 mL) and the organic phase washed with H2O. A further extraction is carried out with 40 mL of 20% Na2CO3 and the weakly alkaline solution is then acidified with HCl conc. and extracted with Et2O (3 x 40 mL). The combined ethereal extracts are evaporated to dryness yielding 8 g (72% of theory) of the title compound; p.eb. 190 ° C / 0.7 mmHg.

Addo 2- (2-methoxy-6-isopropylphenoxy) propionic

(Intermediate IV)

This compound is prepared as described for intermediate III but using ethyl 2-bromopropionate in place of ethyl bromoacetate. The title compound is isolated with a yield of 81% of theory and p.eb. of 165-170 ° C / 0.7 mmHg.

DETAILED PREPARATION OF THE COMPOUNDS OF THE INVENTION

EXAMPLE 1

4-Amino-6.7-dimethoxy-2- (4-benzyl-1-piperazinyl) quinazoline dihydrochloride hemihydrate

A mixture of 4.8 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline (prepared according to: J. Med. Chem. 20, 146-149 (1977)) and 4.2 g of

95% N-benzylpiperazine in 120 mL of isoamyl alcohol is stirred under reflux for 4 h and then cooled. The solid formed is collected by filtration and suspended in 150 mL of H2O and 150 mL of CHCl3 and the mixture is alkalized with 30% NaOH. The organic phase is separated and the aqueous one is re-extracted with CHCl3 (2x50 mL); the combined organic extracts are washed with H2O (2x30 mL), dried over anhydrous Na2SO4 and the solvent evaporated to dryness. The residue is purified by flash chromatography on SiO2 column eluting with CHCl3 / MeOH 100: 3 and the fractions containing the pure base are combined and evaporated to dryness. The residue is dissolved in EtOH and the solution acidified with HCl 4 N in EtOH until complete precipitation of the salt which is collected by filtration and crystallized to MeCN / H2O 7: 3 to give 2.6 g (56% of theory) of the product of the title; m.p .: 265-267 ° C.

EXAMPLE 2

4-Amino-6.7-dimethoxy-2- (4-diphenimethyl-1-piperazinyl) quinazoline dihydrochloride anhydrate

The product is prepared as in Example 1, but using N-diphenylmethylpiperazine (prepared according to: J. Am. Chem. Soc. 71, 2731-2734 (1949)) instead of N-benzylpiperazine and refluxing for 8 h . The crude, collected by filtration, comes

crystallized from 95% EtOH and then dissolved in MeOH, with the addition of HCl dil. and the solution evaporated to dryness. The residue is boiled with H2O to give the title product. Yield: 56% of theory, m.p .:

273-274 ° C.

EXAMPLE 3

4-Amino-6,7-dimethoxy-2- [4- (2.2-diphenylacetyl) -1-piperazinyl] -quinazoline hydrochloride. 0.75H; 0

2.9 g of 4-amino-6,7-dimethoxy-2- (1-piperazinyl) quinazoline (prepared according to: J. Med. Chem. 20, 146-149 (1977)) are added in small portions in about 10 'it's given. to a solution of 4.2 g of 97% dicyclohexylcarbodiimide and 0.12 g of 4-dimethylaminopyridine in 60 mL of CHCl3. The mixture is stirred for 10 'at the same temperature and then added with 2.55 g of 2,2-diphenylacetic acid and further stirred for a further 6 h. The residue obtained from the dry evaporation of the solvent is purified through

flash chromatography on SiO2 column eluting with CHCl3 / MeOH 100: 2. The fractions containing the pure base are combined, the solvents evaporated, the residue dissolved by heat in EtOH 95% and the solution acidified with HCl in EtOH about 4 N. The salt that crystallizes by cooling the solution is collected by filtration and recrystallized from EtOH 90% to give 3.2 g (60% of theory) of the title compound; m.p .: 282-283 ° C.

EXAMPLE 4

4-Amino-6.7-dimethoxy-2- [4- (3.3-diphenylpropionyl) -1-piperazinyl] -quinazoline hydrochloride Method a)

A solution of 7.92 g of 3,3-diphenylpropionic acid in 10 mL of anhydrous DMF is dropped at T.A. in about 15 'to a suspension of 5.8 g of 4-amino-6,7-dimethoxy-2- (1-piperazinyl) quinazoline, 8.42 g of 97% dicyclohexylcarbodiimide and 0.37 g of 4-dimethylaminopyridine in 20 mL of anhydrous DMF. There is a clear solution which is stirred at the same temperature for 5 h, during which a solid (dicyclohexylurea) is formed which is removed by filtration. The solvent is evaporated dry s.v. and the glass residue is made filterable by treatment with 500 mL of Et2O. The crude is purified by flash chromatography on SiO2 column eluting with CHCl3 / MeOH 100: 2. The fractions containing the pure base are combined, the solvents evaporated to dryness, the residue suspended by heat in EtOH and the suspension acidified with HCl in EtOH about 4N until solution.

After cooling, the crystallized salt is collected by filtration and recrystallized from MeCN / H2O 8: 2 to give 5.9 g (55% of theory) of the title compound; m.p .: 239-240 ° C.

Method b)

A solution of 4.4 g of 3,3-diphenylpropionyl chloride (prepared according to: Coll. Czech. Chem. Commun. 25, 736-742 (1960) [CA M, 13055h (I960)]) - In 30 mL of free CHCl3 from EtOH is dropped to T.A. in about 15 minutes to a solution of 5.2 g of 4-amino-6,7-dimethoxy - 2- (1-piperazinyl) quinazoline and 2.8 mL of Et3N in 50 mL of anhydrous DMF. The mixture is stirred at the same temperature for 6 h, the solvents evaporated dry s.v., the residue dissolved in 150 mL of CHCl3 and the solution washed first with 2.5% NaHCO3 and then with H2O and then dried on anhydrous Na2SO4. Continuing as described above in Method a), 4.3 g (43% of theory) of the title compound are obtained.

EXAMPLE 5

4-Amino-6.7-dimethoxy-2- [4 - [(3-benzyloxycarbonylaminino) propionyl - 1-piperazinylquinazoline hydrochloride hemihydrate

This compound is prepared as described in Example 3 but using 3- (benzyloxycarbonylamino) propionic acid instead of 2,2-diphenylacetic acid and maintaining stirring for 5 h. The purification of the crude is carried out by flash chromatography on a SiO2 column with CH2Cl2 / MeOH 100: 5 eluents. The title compound is crystallized from 99% EtOH - Yield: 63% of theory; m.p .: 166-168 ° C.

EXAMPLE 6

4-Amino-6.7-dimethoxy-2- [4 - [(4-benzyloxycarbonylamino) butyryl - 1-piperazinylquinazoline hydrochloride. 1.51H2O

This compound is prepared as described in Example 5, but using 4- (benzyloxycarbonylamino) butyric acid instead of 3- (benzyloxycarbonylamino) propionic acid. The title compound is crystallized from EtOH and melts at 160-169 ° C. Yield: 83% of theory. EXAMPLE 7

4-Amino-6.7-dimethoxy-2- [4- (3-aminopropionyl) -1-piperazininquinazoline dibromohydrate. 1.75 H2O

20 mL of a 30% HBr solution in AcOH is dropped in about 10 minutes in a 4.95 g solution of the prepared compound

in Example 5 in base form, (obtained with conventional methods), in 20 mL of AcOH. The mixture is left under stirring at the same temperature for 2 h and subsequently diluted with 800 mL of Et2O. The precipitate which is collected by filtration is crystallized from EtOH / H2O 4.5: 1 to give 4.7 g (85% of theory) of the title compound; m.p .: 217 ° C.

EXAMPLE 8

4-Amino-6.7-dimethoxy-2- [4- (4-aminobutyryl) -1-piperazinyl] -quinazoline dibromohydrate. 0.25 HgO

This compound is prepared as described in Example 7 but using the product prepared in Example 6 in base form (obtained by conventional methods). The crude is crystallized from MeOH and melts at 272-274 ° C. Yield: 84% of theory.

EXAMPLE 9

4-Amino-6.7-dimethoxy-2-i4 - [(4-methylsulfonylamino) butyrin-1 - piperazinyl] quinazoline hydrochloride

The suspension of 5.3 g of the compound prepared in Example 8 in 50 mL of anhydrous pyridine are dropped at RT. 5.6 mL of Et3N and, after 15 ', 2 mL of methanesulfonyl chloride are dropped at the same temperature and in about 10'. After 1 h of stirring, the reaction mixture is poured into 700 mL of Et2O and the solid formed, collected by filtration, is dissolved in 250 mL of H2O and the alkalized solution by addition of sodium carbonate. The raw base is extracted with chloroform and the residue, obtained by evaporation of the solvent, is made filterable by treatment with 250 mL of Et2O. The solid is then purified by flash chromatography on a SiO2 column eluting in a gradient of CH2Cl2 / MeOH from 100: 5 to 100: 10, The fractions containing the pure base are combined, the solvents evaporated and the residue suspended in 99% hot EtOH; the addition of 4 N HCl in EtOH leads to a clear solution from which, upon cooling, the hydrochloride crystallizes. Further crystallization from 95% EtOH yields 2.1 g (43% of theory) of the title compound; m.p .: 231-233 ° C.

EXAMPLE 10

4-Amino-6.7-dimethoxy-2-H - [(2-dimethylamininoethyl) aminocarbonyl] - 1-piperazinyl] quinazoline dihydrochloride tetrahydrate To a suspension of 4.52 g of N, N'-carbonyldiimidazole in 30 mL of anhydrous THF a solution of 2.48 g of

N, N-dimethylethylenediamine at 97% in 10 mL of anhydrous THF and, after 15 minutes of stirring at RT, a solution of 5.8 g of 4-amino-6,7-dimethoxy-2- is dropped in about 15 minutes. (1-piperazinyl) quinazoline in 250 mL of anhydrous CHCl3. The mixture is stirred at the same temperature for 24 h, added with 2.3 g of Ν, Ν'-carbonyldiimidazole and stirred for another 48 h at the end of which the solvents are evaporated to dryness. The oily residue is purified by flash chromatography on a SiO2 column eluting with CHCl3 / NH3 3N in MeOH 100: 10 and subsequently on a column of Al2O3 eluting with CHCl3 / MeOH 100: 10. The fractions containing the pure product are combined, the solvents evaporated, the residue dissolved in EtOH and the solution acidified with 4N HCl in EtOH. The solution is evaporated to dryness and the crude hydrochloride is crystallized from EtOH-AcOEt 2: 1 to give 5.5 g (50% of theory) of the title compound; m.p .: 206-210 ° C.

EXAMPLE 11

4-Amino-6.7-dimethoxy-2- [4- [2- (benzyloxycarbonylamino) acetyl] - 1-pipérazinyl] quinazoline hydrochloride

This compound is prepared as described in Example 5 but using N-benzyloxycarbonylglycine in place of the acid

3- (benzyloxycarbonylamino) propionic and stirring the mixture for 7 h. The purification of the crude is carried out by flash chromatography on a SiO2 column eluting with a 100: 3 CHCl3 / MeOH mixture. The title compound is crystallized from EtOH / H2O 2: 1. Yield: 79% of theory; m.p .: 263-265 ° C.

EXAMPLE 12

4-Amino-6.7-dimethoxy-2- [4- [2- [2- (benzitoxycarbonylamininoacetylamino] acetyl] -1-piperazinyl] quinazoline hydrochloride hemihydrate This compound is prepared as described in Example 5 but using N-benzyloxycarbonylaminoacetylglycine instead 3- (benzyloxycarbonylamino) propionic acid and DMF as reaction solvent. The crude is purified by flash chromatography on SiO2 column eluting with a 100: 5 CHCl3 / MeOH mixture. The title compound is crystallized from EtOH / H2O 2: 1. Yield: 60% of theory; m.p .:

246-248 ° C.

EXAMPLE 13

4-Amino-6.7-dimethoxy-2- [4- [2-benzoylacetyl) -1-piperazinylquinazoline This compound is prepared as described in Example 5 but using benzoylacetic acid instead of 3- (benzyloxycarbonylamino) propionic acid. The crude is purified by flash chromatography on a SiO2 column eluting with a 100: 3 CH2Cl2 / MeOH mixture. The title compound is crystallized from CH3CN. Yield: 60% of theory; m.p .: 214-215 ° C.

EXAMPLE 14

4-Amino-6.7-dimethoxy-2- [4- (3-hydroxy-3-phenylpropionyl) -1-piperazinyl quinazoline

The solution of 0.43 g of 96% NaBH4 in 4 mL of frozen H2O containing 0.2 mL of 30% NaOH and the mixture is rapidly added to the suspension of 3 g of the compound prepared in Example 13 in 50 mL of MeOH is stirred at T.A. for 8h. Subsequently, 2 g (5x0.4) of NaBH4 are added over a further 8h. The suspension is then diluted with 10 mL of acetone, acidified with dil. HCl, neutralized with sodium bicarbonate solution. at 5% and concentrated s.v .. The aqueous suspension is diluted with H2O and extracted with CHCl3; the organic phase is washed with H2O, dried over anhydrous Na2SO4 and the residue, obtained by evaporation of the solvent, is purified by flash chromatography on a SiO2 column eluting with CH2Cl2 / MeOH 100: 5. The crude, obtained by the union and dry evaporation of the pure fractions, is crystallized by EtOH to give 2.34 g (79% of theory) of the title compound; m.p .: 222 ° C.

EXAMPLE 15

4-Amino-6.7-dimethoxy-2- (4 - [(3-benzoyl) propionine-1-piperazininquinazoline hydrochloride hydrate

This compound is prepared as described in Example 5 but using the 3-benzoylpropionic addo instead of the acid

3- (benzyloxycarbonylamino) propionic. The reaction crude is purified by flash chromatography on SiO2 column eluting with CHCl3 / MeOH 100: 3. The title compound is crystallized from

CH3CN / H2O 65:35 and melts at a temperature> 270 ° C. Yield: 62% of theory.

EXAMPLE 16

4-Amino-6.7-dimethoxy-2- [4- (4-phenyl-4-hydroxybutyril) -1-piperazipinquinazoline maleate (1:11

This compound is prepared as described in Example 14 but using the product synthesized in Example 15 instead of the one synthesized in Example 13 and purifying the reaction crude using CH2Cl2 / MeOH 100: 10 as column eluent mixture. The title compound is obtained with a yield of 67% of theory. after crystallization from EtOH; m.p .: 204-206 ° C ..

EXAMPLE 17

4-Amino-6.7-dimethoxy-2- [4- (3-oxo-3-aminopropionyl) -1-piperazinylquinazoline hydrochloride hydrate

This compound is prepared as described in Example 5 but using 3-oxo-3-aminopropionic acid instead of 3- (benzyloxycarbonylamino) propionic acid and the anhydrous 6: 4 CHCl3 / DMF mixture as reaction solvent. The mixture is stirred at T.A. for a total of 96 hours during which, in portions, another 2 equivalents of 3-oxo-3-aminopropionic acid and 2.5 equivalents of N, N'-dicyclohexylcarbodiimide are added. The purification of the crude is carried out by flash chromatography on a SiO2 column in a gradient of CH2Cl2 / MeOH from 100: 20 to 100: 50. The title compound is crystallized from 88% EtOH. Yield: 23% of theory; m.p .: 241-243 ° C.

EXAMPLE 18

4-Amino-6,7-dimethoxy-2- [4- (2-ethoxycarbonylacetyl) -1-piperaziπyl] -quinazoline hydrochloride

This compound is prepared as described in Example 5 but using mayionic acid monoethyl ester instead of 3- (benzyloxycarbonylamino) propionic acid, and DMF instead of CHCl3 as reaction solvent, for 3 h at RT. The reaction crude is purified by flash chromatography on SiO2 column eluting with 100: 3 CH2Cl2 / MeOH mixture. The title compound is crystallized from 80% EtOH. Yield: 60% of theory; m.p .: 249-250 ° C.

EXAMPLE 19

4-Amino-6.7-dimethoxy-2- [4- (3-n-butylamino-3-oxopropionyl) -1 - piperazinyl-quinazoline hydrochloride

A mixture of 4 g of the compound prepared in Example 18 and 30 mL of n-butylamine in 10 mL of DMSO is heated at 140 ° C for 20 h in a closed flask. The solution is then evaporated to dryness under vacuum, the oily residue taken up with 200 mL of H2O and extracted with CHCl3 (3x50 mL). The glass residue, obtained from the evaporation of the organic phase, is dissolved in 40 mL of 95% EtOH, the solution added with 10 mL of 0.3 N KOH and then heated under reflux for 30 '. The residue obtained from the dry evaporation of the solution is purified by flash chromatography on a SiO2 column, eluting with a CHCl3 / MeOH gradient from 100: 3 to 100: 10. The crude, obtained from the dry evaporation of the fractions containing the pure compound, is dissolved in 75 mL of EtOH, the solution acidified with HCl in EtOH 4 N and the hydrochloride collected, by filtration, crystallized from EtOH 90% to give 2.5 g (53% of theory) of the title compound; m.p .: 260-262 ° C.

EXAMPLE 20

4-Amino-6.7-dimethoxy-2- [4- (phenylaminocarbonylacetyl) -1-piperazinylquinazoline hydrochloride hemihydrate

A mixture of 4 g of the compound prepared in Example 18 and 14 mL of aniline in 6 mL of DMF is heated at 155 ° C for 5.5 h.

The obtained mass is purified as described in Example 19, eluting with a CHCl3 / MeOH gradient from 100: 3 to 100: 4. The crude hydrochloride is crystallized from DMF / H2O 1: 1 to give 1.54 g (31% of theory) of the title compound; m.p .:> 270 ° C.

EXAMPLE 21

4-Amino-6.7-dimethoxy-2- [4- (2-phenoxy-2-methylpropionyl) -1-piperazinylquinazoline hydrochloride. 1.5 H2O This compound is prepared as described in Example 2 but using intermediate I in place of N-diphenylmethylpiperazine and maintaining the reflux heating for 3 h. The precipitate is filtered and crystallized from isopropanol to give the title compound. Yield: 78% of theory, m.p .: 264 ° C.

EXAMPLE 22

4-Amino-6.7-dimethoxy-2- [4- [2- (2-methoxyphenoxy) -2-methylpropionyl] - 1-piperazinyl] quinazoline hydrochloride This compound is prepared as described in Example 1 but using the intermediate II instead of N-benzylpiperazine and refluxing for 5 h and using the AcOEt / MeOH gradient from 100: 0 to 100: 10 as eluent mixture. The title compound is crystallized from 80% EtOH. Yield: 57% of theory; m.p .: 288 ° C (dec.).

EXAMPLE 23

4-Amino-6.7-dimethoxy-2- [4- (2-methoxyphenoxyacetyl) -1-piperazinylquinazoline hydrochloride

This compound is prepared as in Example 3 but using 2-methoxyphenoxyacetic acid in place of the acid

2,2-diphenylacetic and maintaining stirring for 5 h. The residue, obtained after purification on the column, is crystallized from dioxane, then suspended in 85% EtOH and acidified with about 4 N HCl in EtOH. The hydrochloride, collected by filtration, is crystallized from H2O / DMF 2: 1 to give the title compound. Yield: 61% of theory; m.f .:

263-265 ° C.

EXAMPLE 24

4-Amino-6.7-dimethoxy-2- [4 - [(2-methoxy-6-isopropylphenoxylacetyl] - 1-piperazinyl) quinazoline hydrochloride

3.6 mL of SOCl2 is dropped to the boiling solution of 6 g of intermediate III in 30 mL of CCl4 and the mixture is stirred under reflux for 2 h. The oily residue, obtained from the dry evaporation of the reaction mixture, is reacted with 4-amino-6,7-dimethoxy-2 - (1-piperazinyl) quinazoline instead of 3,3-diphenylpropionyl chloride to obtain the compound of title as described in Example 4 (Method b), maintaining stirring for 2 h. The purification is carried out using CHCl3 / MeOH 100: 3 as the column eluent mixture. The title compound is crystallized from EtOH. Yield: 45% of theory; m.p .: 252-254 ° C.

EXAMPLE 25

4-Amino-6.7-dimethoxy-2- [4 - [(2-isopropyl-5-methylphenoxy) acetyl-1 - piperazinyl) quinazoline hydrochloride. 0.25 H2O

This compound is prepared as described in Example 5 but using 2-1sopropyl-5-methenoxyacetic acid (prepared according to: Cesk. Farm. V7, 28-33 (1968) [CA 69 »67041g (1968)]) instead of 2,2-diphenylacetic acid and maintaining stirring for 5 h. The title compound is crystallized from 95% EtOH. Yield: 80% of theory; m.p .: 251-253 ° C.

EXAMPLE 26

4-Amino-6.7-dimethoxy-2- {4- [2- (2-methoxy-6-isopropylphenoxy) propionyl-1-piperazinylquinazoline hydrochloride

To the boiling solution of 4.8 g of Intermediate IV in 25 mL of CCl4, 3 mL of SOCl2 are dropped in about 15 'and the mixture is stirred under reflux for 3 h. The oily residue, obtained from the dry evaporation of the reaction mixture, is used instead of 3,3-diphenylproplonyl chloride to obtain the title compound as described in Example-4 (Method b), maintaining stirring for 2 h. The purification is carried out as described in Example 25 and the title compound is crystallized from EtOH. Yield: 58% of theory; m.p .: 227-229 ° C.

EXAMPLE 27

4-Amino-6.7-dimethoxy-2- [4- (2.6-dimethoxyphenoxy) acetyl-1-piperazinylchinazoline hydrochloride .0.25HgQ

This compound is prepared as described in Example 5 but using 2,6-dimethoxyphenoxyacetic acid (prepared according to the British patent: GB 679,676) instead of 2,2-diphenylacetic acid and using CHCl3 / MeOH 100: 1 as a mixture column eluent. The title compound is crystallized first from 95% EtOH and then from DMF. Yield: 21% of theory; m.p .: 258-260 ° C (dee).

EXAMPLE 28

4-Amino-6.7-dimethoxy-2- (N-benzyl-N-methylamino) quinazoline hydrochloride This compound is prepared as described in Example 1 but using N-methylbenzylamine instead of N-benzylpiperazine and refluxing for 7 h . The crude base is purified by crystallization from EtOH and subsequently redissolved in boiling EtOH and the HCl solution added about 4 N in EtOH. The title compound is obtained in a yield of 62% of theory; m.p. 261-262 "C.

EXAMPLE 29

4-Amino-6.7-dimethoxy-2- (N-methyl-3.3-diphenylpropylamino) quinazoline chloricyrate

This compound is prepared as described in Example 1 but using N-methyl-3,3-diphenylpropylamine (prepared according to German patent DE 925,468) instead of N-benzylpiperazine and refluxing for 12 h. The purification of the crude base is carried out by flash chromatography on a SiO2 column with CHCl3 / MeOH 100: 2 eluents. The title compound is crystallized from 95% EtOH. Yield: 29% of theory; m.p. 258-259 ° C.

EXAMPLE 30

4-Amino-6.7-dimethoxy-2- (1.2.3.4-tetrahydrobenzo [f] isoquinolin-2-11) quinazoline. 0.25 ethanol

This compound is prepared as described in Example V but using 1,2,3,4-tetrahydrobenzo [f] isoquinoline (prepared according to: Indian J. Chem. 1974. 113-116) in place of.

N-benzylpiperazine and heating under reflux for 9 h in the dark and in a nitrogen atmosphere. The purification is carried out by flash chromatography on a SiO2 column eluting with a gradient of CH2Cl2 / NH3-MeOH 5 N from 100: 0.5 to 100: 1.5. The title compound is crystallized from 99% EtOH. Yield: 30% of theory; m.p. 177-180 ° C (dec.).

EXAMPLE 31

4-Amino-6.7-dimethoxy-2- (N-methyl-N- (3- [4- (2-methoxyphahyl) -1 - piperazinylpropylamino) quinazoline dihydrochloride dihydrate This compound is prepared as described in Example 1 but using the N-methyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylamine (prepared according to German patent DE 2,143,730) instead of N-benzylpiperazine and heating under reflux for 12 h. The crude base is purified by flash chromatography on SiO2 column eluting with CHCl3 / NH3-MeOH about 2N 100: 3. The title compound is crystallized from EtOH 92%. Yield: 60% of theory; m.p. 208-210 ° C.

EXAMPLE 32

4-Amino-6.7-dimethoxy-2- (4.4-diphenyl-1-piperidinyl) quinazoline hydrochloride. 0.65 H.0

This compound is prepared as described in Example 1 but using 4,4-diphenylpiperidine (prepared according to:

Arzneim.-Forsch. 233-240 (1984)) instead of N-benzylpiperazine and heating under reflux for 8 h. The crude base is purified by crystallization from OMF-H2O (3: 1). The title compound is crystallized from DMF-H2O (1: 1). Yield: 61% of theory; m.p. > 290 ° C.

EXAMPLE 33

4-Amino-6.7-dimethoxy-2- [1- (3.4-dimethoxybenzyl) -6.7-dimethoxy-1.2.3.4-tetrahydroisoquinolin-2-yl] quinazoline hydrochloride Hydrate A mixture of 3.6 g of 4-amino-2- chloro-6,7-dimethoxyquinazoline, 5,15 g of 1,2,3,4-tetrahydropapaverine (prepared according to: Eur. J. Med. Chem. - Chim. Ther. 9, 233-238 (1974)), 2 , 16 g of potassium iodide and 15 mL of anhydrous DMF is heated under stirring for 8 h at 120-125 ° C. The mixture is poured into 400 mL of H2O and the solid, collected by filtration, is purified by flash chromatography on a SiO2 column eluting with CHCl3 / MeOH 100: 1 and the fractions containing the pure base are combined and evaporated to dryness. The residue is dissolved in MeOH and the solution acidified with HCl in Et2O about 3N until complete precipitation of the salt which is collected by filtration and crystallized from MeOH to give 6.31 g (70% of theory) of the title compound; m.p. 226-230 ° C.

PHARMACOLOGICAL DATA

Methodology

Male Sprague Dawley [Cri: CD "BR] rats weighing 200-300 g body weight, spontaneously hypertensive male rats of the Okamoto strain and female Albino Swiss mice [Cri: CD-1 (ICR) BR] were used for the experiments. 20-30 g body weight The animals were housed with free access to food and water and kept on a forced light-dark cycle at 22-24 ° C until the day of the experiment.

Acute toxicity

Acute toxicity was evaluated after intraoperitoneal and oral administration in female Albino Swiss mice. Four logarithmic scalar doses of each test substance were dissolved or suspended in 0.5% Methocel and administered in a volume of 10 mL / kg to groups of 4 mice / dose. Mortality was recorded 7 days after administration.

Data analysis: LD50 values and their fidudal limits were calculated according to the Weil method (Biometrics 8, 249

(1952)).

Binding of [<3> H] orazosin (αt receptors)

Rat cerebral cortices were homogenized in 50 volumes, relative to the original wet weight, of ice-cold TRIS swab. 50 mM HCl at pH 7.4. The homogenates were centrifuged at 48,000 x g for 10 minutes and the membranes resuspended in the same volume of ice-cold buffer, centrifuged and resuspended two more times. The membranes thus obtained were resuspended in the same volume of buffer, incubated at 37 ° C for 15 min and centrifuged twice with intermediate washing in the cold buffer. The final pellet was resuspended in 50 ml of 50 mM pH 7.4 Tris buffer containing 1% ascorbic acid and 10 μΜ pargiline.

Incubation was carried out by adding 10 µL of [<3> H] prazosin (0.35 nM) and 10 µL of the product solution to be tested (or solvent) to 1 mL of membranes and incubating for 30 min at 25 ° C. L The incubation was stopped by rapid filtration with Whatman GF / B filters using a Brandel cell collector. The filters were washed twice with 15 mL of ice-cold buffer. The radioactivity retained by the filters was measured by liquid scintillation. The non-specific affinity (which is generally 10-30%) was evaluated by adding prazosin 2 μM All products were initially tested in a concentration of 1x10 <-4> M and, in the presence of displacing activity

significant, a complete competition curve was performed. All samples were tested in triplicate.

Data analysis: The competition curves to evaluate the IC50 values were analyzed by non-linear fitting of the logistic curve according to the method reported by De Lean et Al. (Am. J. Physiol. 235. E97 (1978)), using the ALLFIT program (provided by N.I.H.) written for IBM PC.

Evaluation of antihypertensive activity in chronic awake and hypotensive catheterized spontaneous hypertensive (SH) rat in anesthetized normotensive rat

SH rats were surgically prepared at least 24 hours prior to experimentation. Surgery took place during neuroleptoanalgesia or barbiturate anesthesia; the right carotid artery was exposed and a catheter of suitable material and of appropriate size was introduced into the vessel up to the aortic arch. This catheter was tied to the vessel with special sutures and made to run under the skin up to the nape of the animal, where it was externalized and connected to a "Swivel", which allows free movement of the animal, inside the cage, during the experimentation. The end of the catheter was connected to a pressure transducer, which sends the signal to a preamplifier of a polygraph.

For intravenous administrations, a second catheter similar to the previous one was introduced during surgery into the left jugular vein and externalized together with the arterial catheter. Both catheters were filled with appropriate volumes of heparinized saline, to prevent clot or thrombus formation, which would prevent pressure wave registration or administration of intravenous solutions. About 30 min before administration, blood pressure was continuously monitored and the parameters were recorded after administration, at variable times according to the experimental design.

Normotensive rats were surgically prepared at the time of the experiment, after pentobarbital anesthesia. The left carotid artery and right jugular vein were cannulated with catheters of suitable material and appropriate size. The end of the arterial catheter was connected to a pressure transducer, which sends the signal to a preamplifier of a polygraph. About 30 min before administration, blood pressure was continuously monitored and the parameters were recorded after administration, at variable times according to the experimental design.

For intravenous administrations the administration volume was 0.5-1 mL / kg, while for oral administrations it was 5 mL / kg.

Evaluation of results: Regarding the expression of results, blood pressure data were reported as a percentage change from baseline. On these data, at peak effect, a DE25 (dose inducing a 25% decrease in diastolic blood pressure) was evaluated by linear log-dose versus response regression.

For example, the product described in Example 13 showed a DE25 equal to 56 pg / kg after intravenous administration in the normotensive rat and a DE25 equal to 2.42 mg / kg after oral administration in the SHR rat.

Results

The compounds prepared in the examples were examined in accordance with the above methods in relation to the affinity for the α1 receptor ([H] prazosin) and their acute toxicity (LD50).

The results are reported in the following Table, in comparison with the results obtained with the reference standard used.

TABLE

Claims (3)

CLAIMS 1. A compound having the general formula I where B represents one of the following groups: in which: A alternatively represents a valence bond, the -CO- group or the -CONH- group, each of which is represented meaning that the left side is the part connected to the heterocyclic ring and the right side the part connected to the alkyl chain; R1 and R2 are the same or different and independently represent a hydrogen atom or a linear or branched alkyl group having from 1 to 4 carbon atoms; n is 0 or 1; m is an integer from 0 to 4 and R represents an aryl or diarylmethyl or aroyl or aryl (hydroxy) methyl or alkyloxycarbonyl or aryloxy group unsubstituted or optionally substituted with one or more alkoxy, linear or branched alkyl groups having from 1 with 4 carbon atoms or a group of formula -CONHR3 or -NCR4) R5. where is it: - R3 represents a hydrogen atom or a linear or branched alkyl group, having from 1 to 4 carbon atoms, or an aryl group; - R4 and R5 can be the same or different and independently represent a hydrogen atom or a linear or branched alkyl group having from 1 to 4 carbon atoms or a benzyloxycarbonyl or methanesulfonyl or benzyloxycarbonylglycinoyl group; in which: Alk represents a linear alkyl group having from 1 to 3 carbon atoms and Z represents a phenyl or benzhydryl or 4- (2-methoxyphenyl) -1-piperazinyl group; or an enantiomer, diastereomer, N-oxide or addition salt thereof with a pharmaceutically acceptable acid. 2. Any of the following compounds: 4-Amino-6,7-dimethoxy-2- (4-benzyl-1-piperazinyl) quinazoline, 4-Amino-6,7-dimethoxy-2- (4-diphenylmethyl-1-piperazinyl) quinazoline, 4-Amino-6,7-dimethoxy-2- [4- (2,2-diphenylacetyl) -1-piperazinyl] -chinazoline, 4-Amino-6,7-dimethoxy-2- [4- (3,3-diphenylpropionyl) -1-piperazinyl] -quinazoline, 4-Amino-6,7-dimethoxy-2- {4 - [(3-benzyloxycarbonylamino) propionyl] - 1-piperazinyl} quinazoline, 4-Amino-6,7-dimethoxy-2- {4 - [(4-benzyloxycarbonylamino) butyryl] - 1-piperazinyl} quinazoline, 4-Amino-6,7-dimethoxy-2- [4- (3-aminopropionyl) -1-piperazinyl] -quinazoline 4-Amino-6,7-dimethoxy-2- [4- (4-aminobutyryl) -1-piperazinyl] -quinazoline, 4-Amino-6,7-dimethoxy-2- {4 - [(4-methylsulfonylamino) butyryl] -1-piperazinyl] quinazoline, 4-Amino-6,7-dimethoxy-2- {4 - [(2-dimethylaminoethyl) aminocarbonyl] -1 - piperazinyl] quinazoline, 4-Amino-6,7-dimethoxy-2- {4- [2- (benzyloxycarbonylamino) acetyl] -1 - piperazinyl] quinazoline, 4-Amino-6,7-dimethoxy-2- {4- [2- [2- (benzyloxycarbonylamino) -acetylamino] acetyl] -1-piperazinyl} quinazoline, -Amino-6,7-dimethoxy-2- [4- (2-benzoylacetyl) -1-piperazinyl] quinazoline, -Amino-6,7-dimethoxy-2- [4- (3-1 hydroxy-3-phenylpropionyl) -1-piperazinyl] quinazoline, -Amino-6,7-dimethoxy-2- {4 - [(3-benzoyl) propionyl] -1-piperazinyl} quinazoline, -Amino-6,7-dimethoxy-2- [4- (4-phenyl-4-hydroxybutyril) -1-piperazinyl] -quinazoline, -Amino-6,7-dimethoxy-2- [4- (3-oxo-3-aminopropionyl) -1-piperazinyl] -quinazoline, -Amino-6,7-dimethoxy-2- [4- (2-ethoxycarbonylacetyl) -1-piperazinyl] -quinazoline, -Amino-6,7-dimethoxy-2- [4- (3-n-butylamino-3-oxopropionyl) -1-piperazinyl] quinazoline, -Amino-6,7-dimethoxy-2- [4- (phenylaminocarbonylacetyl) -1-piperazinyl] -quinazoline, -Amino-6,7-dimethoxy-2- [4- (2-phenoxy-2-methylpropionyl) -1-piperazinyl] quinazoline, -Amino-6,7-dimethoxy-2- {4- [2- (2-methoxyphenoxy) -2-methylpropionyl-1-. piperazinyl} quinazoline, -Amino-6,7-dimethoxy-2- [4- (2-methoxyphenoxyacetyl) -1-piperazinyl] -quinazoline, -Amino-6,7-dimethoxy-2- {4 - [(2-methoxy-6-isopropylphenoxy) acetyl] -1 - piperazinyl} quinazoline, -Amino-6,7-dimethoxy-2- {4 - [(2-1sopropyl-5-methylphenoxy) acetyl] -1 - piperazinyl] quinazoline, 4-Amino-6,7-dimethoxy-2- {4- [2- (2-methoxy-6-isopropylphenoxy) -propionyl] -1-piperazinyl} quinazoline, 4-Amino-6,7-dimethoxy-2- [4- (2,6-dimethoxyphenoxy) acetyl-1 - piperazinyl] quinazoline, 4-Amino-6,7-dimethoxy-2- (N-benzyl-N-methylaminino) quinazoline, 4-Amino-6,7-dimethoxy-2- (N-methyl-3,3-diphenylpropylamino) quinazoline, 4-Amino-6,7-dimethoxy-2- (1,2,3,4-tetrahydrobenzo [f] isoquinolin-2-yl) -quinazoline, 4-Amino-6,7-dimethoxy-2- {N-methyl-N- {3- [4- (2-methoxyphenyl) -1 - piperazinyl] propyl} amino} quinazoline, 4-Amino-6,7-dimethoxy-2- (4,4-diphenyl-1-piperidinyl) quinazoline 4-Amino-6,7-dimethoxy-2- [1- (3,4-dimethoxybenzyl) -6,7-dimethoxy-1,2,3,4 - tetrahydroisoquinolin-2-yl] quinazoline. 3. A pharmaceutical composition in which the active ingredient is constituted by a compound according to the preceding claims, or by an enantiomer, diastereomer, N-oxide or pharmaceutically acceptable salt of such compound, mixed with pharmaceutically acceptable excipients, diluents or carriers.